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当代阿耳茨海默病研究

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Research Article

Exendin-4 通过增加脑胰岛素合成改善糖尿病小鼠的认知功能

卷 18, 期 7, 2021

发表于: 29 September, 2021

页: [546 - 557] 页: 12

弟呕挨: 10.2174/1567205018666210929150004

价格: $65

摘要

背景与目的：2 型糖尿病 (T2D) 患者更容易患上阿尔茨海默病 (AD)。我们之前已经表明，胰高血糖素样肽-1 受体激动剂 exendin-4 (Ex-4) 通过上调胰岛素信号减少 T2D 动物的 tau 过度磷酸化，并且外周注射的 Ex-4 增加了 T2D 大脑中的胰岛素水平。本研究旨在进一步阐明大脑中升高的胰岛素是否是在Ex-4的作用下由神经细胞产生的。 方法：在高糖或正常培养下用Ex-4处理神经元细胞株HT22，检测胰岛素阳性细胞数及胰岛素合成相关基因的表达水平。 db/db小鼠外周注射Ex-4和/或IntraCerebroVentricular (ICV)注射siRNA以抑制胰岛素合成相关基因的表达，并进行行为测试。最后，检测 db/db 小鼠的血浆葡萄糖、脑脊液 (CSF) 葡萄糖、CSF 胰岛素、tau 的磷酸化、AKT 和 GSK-3β 的磷酸化。 结果：我们发现Ex-4在高糖环境下促进了胰岛素合成相关基因的表达，并诱导了胰岛素阳性HT-22神经元细胞的明显增加。 Ex-4 的外周注射改善了 db/db 小鼠的认知功能并增加了大脑胰岛素水平，从而激活了大脑胰岛素信号传导，随后减轻了 tau 过度磷酸化。然而，当注射siRNA-neurod1阻断胰岛素合成时，db/db小鼠的认知功能在Ex-4的作用下不再有改善。而且，大脑胰岛素水平下降到极低的水平，tau蛋白的磷酸化水平显着增加。 结论：本研究表明，Ex-4 通过促进脑胰岛素合成、随后激活脑胰岛素信号传导和缓解 tau 过度磷酸化来改善认知功能。

关键词: 2 型糖尿病、阿尔茨海默病、胰高血糖素样肽-1、胰岛素、exendin-4、db/db。

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